Long non-coding RNAs (lncRNAs) are transcribed and expressed in a developmentally and disease-regulated manner and their function in the genome is a source of great interest. The primary focus of this proposal is to identify and characterize metastatic melanoma specific lncRNAs and conduct mechanistic studies to demonstrate their disease relevance to human melanomas. Our interest in the role of lncRNA to melanoma arises from our recent demonstration (Khaitan et al., Cancer Research 2011) of siRNA-mediated knock-down of a melanoma upregulated long noncoding RNA causes defects in cell growth, motility and differentiation, and induces apoptosis of melanoma cells lines, suggesting a role for long noncoding RNAs in melanoma development. Recently, we have identified a group of differentially expressed lncRNAs in distant metastatic melanoma patients' samples compared to normal skin. We strongly believe that this information is useful to understand melanoma metastasis and to develop diagnostic and therapeutic tools against this form of cancer. In this application, we propose experiments to extend our preliminary analysis of lncRNA expression to a larger patient population, and confirm the statistical significance of our preliminary data. Based on our preliminary observations, we hypothesize that differentially expressed lncRNAs are useful biomarkers for melanoma detection in humans. We propose the following Specific Aims to test our central hypothesis. Specific Aim 1: To test the hypothesis that differentially expressed melanoma-specific lncRNAs are useful biomarkers for melanoma detection in humans. Specific Aim 2: To identify the molecular function of melanoma upregulated lncRNA, AK023647. The major impact of this study is to demonstrate for the first time the involvement of lncRNA in development of melanoma, beyond the boundaries of protein-coding genes. The proposed study has the potential to have a high-impact on our understanding of melanoma development.